Preparation And Evaluation Of Propranolol Hydrochlorid Cubic Liquid Crystal Gel

Infantile hemangioma is a most common childhood benign tumor.Commonly used drugs for the treatment of hemangioma include glucocorticoids,hardener,antitumor drugs,anti-angiogenesis drugs and immune modulators.Oral propranolol was proposed to treat infantile hemangioma by Léauté-Labrèze in 2008.Although oral propranolol is effective in treatment of hemangioma,there are untoward effects such as bradycardia,hypotension and hypoglycemia,resulting in the poor compliance for infants.More than that,oral propranolol also has matters such as liver first pass effect and low bioavailability.This project is proposed to develop propranolol hydrochlorid cubic liquid crystal gel to solve the above-mentioned problems.Propranolol hydrochloride cubic liquid crystal could reduce administration frequency and increase the compliance for infants resulting from the cubic liquid crystal has sustained-release effect.In addition,propranolol hydrochloride loaded in cubic liquid crystal can overcome the poor photostabiity of crude drug.In this study,a HPLC analysis method was established to determine the content of propranolol hydrochloride in the gel,as well as the content determintion in vitro release test and in vitro percutaneous test.This method is concise and accurate,with strong specificity,good reproducibility and high sensitivity.Propranolol hydrochloride cubosomes were prepared by the Bottom-up method.Entrapment efficiency and average particle size as evaluaing indexes,the single factor test for preparation procedure and prescription of propranolol hydrochloride cubsomes was used to determine the best preparation procedure.The optimal preparation procedure: stirring rate is 600 r·min-1,stirring temperature is 20?,stirring time is 1h,homogenization pressure is 800 bar,homogenization number is 7.The optimization of prescription was achieved by central composite design-response surface methodology.The optimal prescription: propranolol hydrochloride 3.5 g,glyceryl monooleate 9 g,poloxamer 407 1.5 g,and add purified water to 100 g.The morphology of cubosomes were observed by transmission electron microscope,the results showed that cubsomes were spherical,smooth,uniform distribution and not adhesion.The particle size and zeta potential of propranolol hydrochloride cubsomes were measured by the laser particle size instrument,the mean diameter was 106.17±4.03 nm,zeta potential was-29.73±1.23 mV.The entrapment efficiency of cubsomeswas 52.92 ± 1.61% and drug loading was 3.26 ± 0.09%.The results of polarizing microscope and small Angle X-ray scattering were that internal structure was cubic phase and lattice was Pn3 m.The exist form of propranolol hydrochloride in cubic liquid crystal was determined by differential scanning calorimetry,the result of storage stability showed that cubosomes were stable.In vitro drug release properties was investigated in pH7.4 PBS as dissolution media and the model equation fitting was established.In vitro percutaneous permeation test method was established with physiological saline as receiving media,the accumulative permeation quantity as evaluating index,the penetration enhancers were investigated.The final gel prescription was as follow:propranolol hydrochloride 3 g,glyceryl monooleate 7.71 g,poloxamer 407 1.29 g,purified water 64.9 g,chitosan450 1.6 g,PEG4000 10 g,azone 1g,glycerinum 10 g,glacial acetic acid 0.4 g,ethylparaben 0.1 g.The hydrochlorid propranolol cubic liquid crystal gel had favorable viscosity,homogeneity and apreadability.The pH of the gel was around 5.51,the viscosity was in 85~90 Pa·s,the contenr of propranolol hydrochloride in gel was around 30mg·g-1,the accumulative permeation amount of propranolol hydrochloride in vitro was in 260~300?g·cm-2.The stability of crude drug and gel were examined,the results showed that propranolol hydrochloride had poor photostabiity,and the home-made propranolol hydrochloride cubic liquid crystal gel was relatively stable under the condition of high temperature,high humidity and strong light irradiation.The results proved that propranolol hydrochloride loaded in cubic liquid crystal could overcome the poor photostablity of crude drug.Three batches of the home-made gel samples showed good stabilities in the 6 months accelerated test and long-term test for 6months.The results of the safety tests that the the home-made gel was smeared on experimental animal skins showed that propranolol hydrochloride cubic liquid crystal gel had no skin irritation or allergic reaction.